Abstract
BackgroundAlterations to cellular and molecular programs with brain aging result in cognitive impairment and susceptibility to neurodegenerative disease. Changes in DNA methylation patterns, an epigenetic modification required for various CNS functions are observed with brain aging and can be prevented by anti-aging interventions, but the relationship of altered methylation to gene expression is poorly understood.ResultsPaired analysis of the hippocampal methylome and transcriptome with aging of male and female mice demonstrates that age-related differences in methylation and gene expression are anti-correlated within gene bodies and enhancers. Altered promoter methylation with aging was found to be generally un-related to altered gene expression. A more striking relationship was found between methylation levels at young age and differential gene expression with aging. Highly methylated gene bodies and promoters in early life were associated with age-related increases in gene expression even in the absence of significant methylation changes with aging. As well, low levels of methylation in early life were correlated to decreased expression with aging. This relationship was also observed in genes altered in two mouse Alzheimer’s models.ConclusionDNA methylation patterns established in youth, in combination with other epigenetic marks, were able to accurately predict changes in transcript trajectories with aging. These findings are consistent with the developmental origins of disease hypothesis and indicate that epigenetic variability in early life may explain differences in aging trajectories and age-related disease.
Highlights
Epigenetic modifications, chromatin, and direct DNA modifications are key genomic regulatory processes required for proper development [1], gene imprinting [2,3,4], X chromosome inactivation [5,6,7], gene expression regulation [8], and genomic organization [9,10,11]
No differences in average methylation levels between males and females were observed. These agree with previous findings that there is no hypomethylation with aging in the murine hippocampus [49, 50]
Differences in methylation in these models were not examined, a potential difference in methylation due to Alzheimer’s disease (AD) pathology as a driving mechanism of differential gene regulation cannot be excluded; our findings suggest that genes differentially regulated with neurodegeneration may be more susceptible to change due to their methylation profile in a manner similar to that observed for genes differentially expressed with aging
Summary
Epigenetic modifications, chromatin, and direct DNA modifications are key genomic regulatory processes required for proper development [1], gene imprinting [2,3,4], X chromosome inactivation [5,6,7], gene expression regulation [8], and genomic organization [9,10,11]. Dysregulated epigenetic control with aging has been proposed as an etiological factor common to age-related diseases ranging from diabetes to DNA methylation changes with aging demonstrate both tissue specificity and conservation across tissues depending on the specific genomic location [28,29,30]. Tissue-specific DNA methylation changes with aging on the other hand may underlie organ/cell-specific deficits. In the liver, gene body hypermethylation occurs primarily in genes involved in lipid metabolism [33], while in the brain age-related methylation changes occur in genes involved in synaptic transmission and cellular integrity [26]. Changes in DNA methylation patterns, an epigenetic modification required for various CNS functions are observed with brain aging and can be prevented by anti-aging interventions, but the relationship of altered methylation to gene expression is poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
